keratan-sulfate and Shock--Septic

Glycosaminoglycans (GAGs) are negatively charged polysaccharides present, e.g., on the luminal face of the blood vessels as heparan sulphate (HS) and hyaluronic acid (HA), in the interstitium as HA, and in neutrofils and plasma as chondroitin sulphate (CS) and HA. Total plasma levels of GAG are increased in human septic shock, but the origin and pathophysiological implications are unclear. In order to determine the source of circulating GAG in sepsis, we compared plasma levels of HS, HA, CS and keratan sulphate (KS) in patients with septic shock and controls.. HS and KS were measured with enzyme-linked immunosorbent assay, and HA and CS disaccharides with liquid chromatography tandem mass spectrometry in plasma obtained from patients admitted to intensive care fulfilling criteria for septic shock as well as from matched control patients scheduled for neurosurgery.. Median levels of HS and HA were fourfold increased in septic shock and were higher in patients that did not survive 90 days (threefold and fivefold for HS and HA, respectively). Median CS levels were unaltered, while KS levels were slightly decreased in sepsis patients. HS and HA levels correlated with levels of interleukin-6 and interleukin-10. Except for HA, GAG levels did not correlate to liver or kidney sequential organ function score.. Median plasma level of HS and HA is increased in septic shock patients, are higher in patients that do not survive, and correlates with inflammatory activation and failing circulation. The increased levels could be due to vascular damage.

Topics: Adult; Aged; Aged, 80 and over; C-Reactive Protein; Chondroitin Sulfates; Disaccharides; Enzyme-Linked Immunosorbent Assay; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Indicators and Reagents; Interleukin-10; Interleukin-6; Keratan Sulfate; Male; Middle Aged; Multiple Organ Failure; Peroxidase; Sepsis; Shock, Septic; Survival

Lumican is an extracellular matrix protein modified as a proteoglycan in some tissues. The core protein with leucine-rich repeats, characteristic of the leucine-rich-repeat superfamily, binds collagen fibrils and regulates its structure. In addition, we believe that lumican sequestered in the pericellular matrix interacts with cell surface proteins for specific cellular functions. Here we show that bacterial lipopolysaccharide sensing by the Toll-like receptor 4 signaling pathway and innate immune response is regulated by lumican. Primary cultures of lumican-deficient (Lum(-/-)) macrophages show impaired innate immune response to lipopolysaccharides with lower induction of tumor necrosis factor alpha (TNFalpha) and interleukin-6. Macrophage response to other pathogen-associated molecular patterns is not adversely affected by lumican deficiency, suggesting a specific role for the lumican core protein in the Toll-like receptor 4 pathway. An exogenous recombinant lumican core protein increases lipopolysaccharide-mediated TNFalpha induction and partially rescues innate immune response in Lum(-/-) macrophages. We further show that the core protein binds lipopolysaccharide. Immunoprecipitation of lumican from peritoneal lavage co-precipitates CD14, a cell surface lipopolysaccharide-binding protein that is involved in its presentation to Toll-like receptor 4. The Lum(-/-) mice are hypo-responsive to lipopolysaccharide-induced septic shock, with poor induction of pro-inflammatory cytokines, TNFalpha, and interleukins 1beta and 6 in the serum. Taken together, the data indicates a novel role for lumican in the presentation of bacterial lipopolysaccharide to CD14 and host response to this bacterial endotoxin.

Topics: Animals; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Collagen; Extracellular Matrix; Female; Immunity, Innate; Interleukin-6; Keratan Sulfate; Lipopolysaccharide Receptors; Lipopolysaccharides; Lumican; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; Mice, Mutant Strains; Shock, Septic; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha